Process for preparing naproxen

ABSTRACT

Process for preparing Naproxen via a sequence of a stereospecific reactions which comprises: condensation of 1-chloro-2-methoxy-naphthalene with a (S)-2-halo-propionyl halide according to the Friedel-Crafts reaction, ketalization of the thus obtained (S)-2-halo-1-(5&#39;-chloro-6&#39;-methoxy-2&#39;-naphthyl)-propan-1-one, rearrangement of said ketal to aford an ester, hydrolysis of the ester and removal of the chlorine atom in 5-position by hydrogenolysis.New (S) 2-halo-1-(5&#39;-chloro-6&#39;-methoxy-2&#39;-naphthyl)-propan-1-ones.

RELATED APPLICATION

This application is a division of application Ser. No. 732,735, filedMay 10, 1985.

This invention relates to a process for the preparation of Naproxen viaa sequence of stereospecific reactions which comprises: condensation of1-chloro-2-methoxy-naphthalene with a (S)-2-halo-propionyl halideaccording to the Fridel-Crafts reaction, ketalization of the thusobtained (S)-2-halo-1-(5'-chloro-6'-methoxy-2'-napthyl)-propan-1-one,rearrangement of said ketal to afford an ester, hydrolysis of the esterand removal of the chlorine atom in 5-position by hydrogenolysis. Insaid sequence hydrogenolysis of the chlorine atom can precede hydrolysisof the ester.

Naproxen (Merck Index, IX ed., page 834) is a known drug endowed withantiinflammatory, analgesic and antipyretic activity.

Of the two possible enantiomers only the (S) enantiomer is used fortherapeutic purposes. The majority of known synthetic routes call forthe preparation of the racemate, separation of the (S) enantiomer,racemization of the (R) enantiomer, further separation of the (S)enantiomer and so on.

These steps greatly increase the production costs of Naproxen.

A need is therefore very strongly felt for a stereospecific synthesiswhich would avoid the inconvenience mentioned above.

European patent application No. 82303068.9 describes a process whichwould provide for the preparation of optically active arylalkanones bythe Friedel-Crafts reaction according to the following diagram: ##STR1##where Ar is an aromatic group, R is an aliphatic group, X is a halogenor a sulfonyloxy group and Y is a halogen.

In the aforementioned European patent application it is maintained thatthe very well-known Friedel-Crafts reaction is suitable for preparingall the innumerable optically active arylakanones embraced by formula Iwithout any exceptions and it is also maintained that this isunexpected.

European patent application No. 82306603.0 describes the preparation ofsaid optically active arylalkanones of formula I with the equallywell-known Grignard reaction. Here again there is the assertion that theresult is unexpected.

According to both said European patent applications subsequent treatmentof optically active arylalkanones to give the corresponding opticallyactive arylalkanoic acids can follow the route described in Europeanpatent application No. 81200210.3.

Even though European patent application No. 82303068.9 indicatesNaproxen as one of the optically active arylalkanoic acids which can beprepared with the process described therein, in reality said patentapplication does not give any examples thereof.

European patent application No. 82306603.0 gives several examples of astereoselective synthesis of Naproxen but this method suffers from thedifficulty, well-known to the artisan, in performing the Grignardreaction on an industrial scale, and calls for the use of2-bromo-6-methoxy-naphthalene, the synthesis of which is considerablymore complex than that of 1-halo-2-methoxy-naphthalenes.

In 1970 A. P. Desai et al (3. Indian Chem. Soc., Vol. 47, No. 2, pages117-8; 1970) had found that optically active arylalkanones can beprepared according to both the Friedel-Crafts and the Grignard reactionfrom an aromatic compound and an optically active derivative of analkanoic acid. In other words, the conditions under which theFriedel-Crafts and the Grignard reaction are performed may not causeracemization of the optically active alkanoic acid derivative which isused.

In view of the above mentioned teachings it might seem easy to prepareNaproxen through optically active compounds of the formula ##STR2##where X' is Cl or Br, obtained with the Friedel-Crafts reaction.

Surprisingly, however, several attempts (see examples 4 and 5 below)made to prepare compounds II by the Friedel-Crafts reaction according tothe following diagram: ##STR3## where X' and X", the same or different,are chlorine or bromine; did not yield compounds II and this issurprising considering that the halide of the propionic acid affords thedesired product with practically quantitative yields according to thefollowing diagram: ##STR4##

It has now been found that the compounds of formula ##STR5## where X'has the above meanings, can be prepared in optically active form withhigh yields according to the Friedel-Crafts reaction and that they areparticularly useful in intermediates in the stereospecific synthesis ofNaproxen.

And this is all the more surprising considering that, when theFriedel-Crafts reaction is carried out by reacting a compound of formulaIII with 1-bromo-2-methoxy-naphthalene (see example 3, below), onlysmall quantities are obtained of the bromine derivative analogous of thecompound of formula IV, together with various other compounds from whichthe compound of formula IV can be separated only with much difficulty.

The object of the present invention is hence a stereospecificpreparation, process for Naproxen which comprises the preparation inaccordance with the Friedel-Crafts reaction, of an optically activecompound of formula IV.

Another object of the present invention consists of the new opticallyactive compounds of formula IV.

Other objects and advantages of the present invention will becomeapparent from the following detailed description and from the examples.

The stereospecific preparation for Naproxen according to the presentinvention is accomplished in the following steps:

(a) reaction of the 1-chloro-2-methoxy-naphthalene with an opticallyactive compound of formula III to give an optically active compound offormula IV having absolute configuration (S);

(b) ketalization of the compound of formula IV under nonracemizingconditions with an alcohol having from 1 to 12 carbon atoms to give anoptically active ketal having absolute configuration (S);

(c) rearrangement of the ketal into an optically active ester havingabsolute configuration (S).

(d) hydrolysis of this last under nonracemizing conditions;

(e) removal by means of hydrogenolysis under nonracemizing conditions ofthe chlorine atom in 5-position.

The sequence given above is not binding since step (3) can precede step(d).

Step (a) is carried out in the presence of a suitable catalyst, such asaluminum chloride, preferably in the presence of a suitable solvent andat a temperature from 10° C. to 35° C.

Step (b) is preferably carried out with a lower aliphatic alcohol, suchas methanol, in the presence of the corresponding orthoformate and usingan excess of alcohol or orthoformate, which also act as solvents. Tothis mixture can also be added another solvent which promotes even moredissolving of the substrate. Suitable solvents are aromatichydrocarbons, such as benzene and toluene. Preferred reactiontemperature is that of reflux of the reaction mixture.

Step (c) is preferably carried out in the presence of a suitablecatalyst. Examples of suitable catalysts are inorganic derivatives ofzinc, such as zinc chloride, bromide and oxide.

Concerning step (d) it was seen that in basic conditions theracemization speed of the ester is greater than hydrolysis speed. It istherefore preferred to operate under acid conditions, however avoidingagents, such as hydrobromic acid, or conditions which cause partial ortotal demethylation of the methoxy group. Suitable conditions are thoseobtained using hydrochloric acid and a suitable solvent, such asacetone, at temperatures below 60° C. Similarly, the reaction can beperformed with formic acid or acetic acid in the presence of catalyticamounts of a mineral acid at temperatures below 60° C.

When the hydrogenolysis (step e) is performed on the acid compound, itcan be carried out under basic, neutral or acid conditions usinghydrogen or a hydrogen transferrer in the presence of appropriatecatalysts and suitable solvents on condition, however, of not usingalcohols (when operating under acid conditions) to avoid the formationof the corresponding ester. When the hydrogenolysis is performed on theester compound, i.e. before step (d), care must be taken to avoid basicconditions to prevent racemization of the ester. In general care must betaken to perform the hydrogenolysis under the mildest conditionscompatible with the system used.

The expression "nonracemizing conditions" is used in this description toindicate that racemization is reduced to a minimum and that theformation of enantiomer R usually does not exceed five percent.

The following examples illustrate the invention without limiting it inany way.

EXAMPLE 1

To a mixture of 7.3 g (54.7 mmol) of AlCl₃ in a 25 ml of methylenechloride kept at 20°-25° C. are gradually added 7.2 g (56.7 mmol) of(S)-2-chloro-propionyl-chloride ##EQU1## +5.44° (pure liquid; l=1 dm)and 7.0 g (36.4 mmol) of 1-chloro-2-methoxy-naphthalene. After further 4hrs at 20°-25° C., the mixture is hydrolized and worked up accordingusual procedures to give 10.2 g of a crude product which afterrecrystallization from a mixture heptane/methanol (3/2, v/v) affords 6.2g (yield, 60%) of (S)2-chloro-1-(5'-chloro-6'-methoxy-2'-napthyl)-propan-1-one melting at123° C., ##EQU2## +108.5 (C=0.8; CHCl₃). NMR (CDCl₃, TMS as reference):1.5 (3H, d, CHCH₃), 3.7 (3H, s, (OCH₃), 5.0 (1H, q, CH), 8.0-6.5 (5H, m,aromatic hydrogens), mass (m/e): 282-284 (M⁺, 21%), 219-21 (100%).

EXAMPLE 2

Repeating the procedure of Example 1 but replacing (S)-2-bromo-propionylchloride for (S)-2-chloro-propionyl chloride are obtained 10.5 g (yield,89%) of (S)-2-bromo-1-(5'-chloro-6'-methoxy-2'-naphthyl)-propan-1-one.

EXAMPLE 3

Repeating the procedure of Example 1, but replacing1-chloro-2-methoxy-naphthalene by 1-bromo-2-methoxy-naphthylene yields1.7 g (yield, 15%) of(S)-2-chloro-1-(5'-bromo-6'-methoxy-2'-naphthyl)-propan-1-one.

EXAMPLE 4

Repeating the procedure of Example 1, but replacing1-chloro-2-methoxy-naphthalene, by 2-methoxy-naphthalene yields a crudeproduct consisting mainly of (S)2-chloro-1-(2'-methoxy-1'-naphthyl)-propan-1-one wherein the ratiobetween this compound and the corresponding (6'-methoxy-2'-naphthyl)isomer is about 93/7 (HPLC analysis).

EXAMPLE 5

Repeating the procedure of Example 2, but replacing1-chloro-2-methoxy-naphthalene by 2-methoxy-naphthalene yields a crudeproduct consisting mainly of (S)2-bromo-1-(2'-methoxy-1'-naphthyl)-propan-1-one wherein the ratiobetween this compound and the corresponding (6'-methoxy-2'-naphthyl)isomer is about 70/30.

EXAMPLE 6

A mixture of 6.2 g (21.9 mmol) of(S)-2-chloro-1-(5'-chloro-6'-methoxy-2'-naphthyl)-propan-1-one, obtainedaccording to Example 1, 60 ml of methanol, 13 ml of toluene, 14.5 g(135.8 mmol) of trimethylorthoformate and of 1.2 g of 96% sulfuric acidis refluxed for 23 hours while distilling about 25% of the solvent. Whenthe reaction is over, the mixture is neutralized with an aqueoussolution of sodium carbonate. The toluene layer is separated andconcentrated to give 7.0 g of(S)-2-chloro-1,1-dimethoxy-1-(5'-chloro-6'-methoxy-2'-naphthyl)-propan;a sample is purified by chromatography on silica gel (eluents: petroleumether/ethyl acetate 90/10), m.p. 106° C., ##EQU3## +25.0 (C=1.0; CHCl₃).

EXAMPLE 7

A mixture of 6.0 g (18.2 mmol) of(S)-2-chloro-1,1-dimethoxy-1-(5'-chloro-6'-methoxy-2'-naphthyl)-propane,obtained according to Example 6, 55 mg (0.4 mmol) of zinc chloride andof 120 ml of toluene is refluxed while distilling the solvent until theinternal temperature is of about 120° C. After 3 hours the reactionmixture is treated with animal charcoal, filtered and concentrated toafford 5.1 g of methyl(S)-2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionate; a sample ispurified by chromatography on silica gel (eluents: heptane/ethyl acetate95/5), m.p. 102° C. ##EQU4## +60.78 (C=1.0; CHCl₃).

Similar results are obtained replacing zinc bromide for zinc chloride.

EXAMPLE 8

Repeating the procedure of Example 7 but replacing zinc chloride by zincoxide, as catalyst yields 5.1 g of methyl(S)-2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionate, ##EQU5## +62.87(C=1.0; CHCl₃) after crystallization from heptane.

EXAMPLE 9

A mixture of 3.0 g (10.8 mmols) of methyl (S)2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionate, obtained according tothe procedure of Examples 7, of 20 ml of 37% HCl and of 20 ml of acetoneis refluxed for 3 hours. After the usual treatments 2.6 g of (S)2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionic acid, m.p. 158° C.,##EQU6## +48.59 (C=1.0; CHCl₃), are obtained.

EXAMPLE 10

A mixture of 0.94 g (3.6 mmol) of(S)-2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionic acid, obtainedaccording to Example 9, of 0.8 ml (8.0 mmol) of 30% sodium hydroxide andof 90 mg of Raney Nickel in 7 ml of water, is admixed slowly at 75° C.with 1 ml (25.0 mmol) of 80% hydrazine hydrate. After 3 hours themixture is filtered and made acid up to pH 1 to give 0.7 g of(S)-2-(6'-methoxy-2'-naphthyl)-propionic acid, ##EQU7## +64.36 (C=1.0;CHCl₃).

EXAMPLE 11

A mixture of 3.0 g (10.8 mmol) of methyl(S)-2-(5'-chloro-6'-methoxy-2'-naphthyl)-propionate, obtained accordingto Example 8, and of 0.3 g of 10% Pd/C in 20 ml of methanol ishydrogenated at atmospheric pressure and at room temperature to give 2.4g of methyl (S)-(6'-methoxy-2'-naphthyl)-propionate, ##EQU8## +72.4(C=1.0; CHCl₃).

EXAMPLE 12

2.0 g (8.2 mmol) of methyl (S)-2-(6'-methoxy-2'-naphthyl)-propionate,obtained according to Example 11, are hydrolized according to theprocedure of Example 9 to give 1.8 g of(S)-2-(6'-methoxy-2'-naphthyl)-propionic acid, ##EQU9## +63.40 (C=1.0;CHCl₃).

What is claimed is:
 1. An optically active arylalkanone of formula:##STR6## wherein X' is chlorine or bromine having (S) absoluteconfiguration.
 2. The optically active arylalkanone according to claim 1wherein X' is chloro.
 3. The optically active arylalkanone according toclaim 1 wherein X' is bromo.